The overall goal of this research program is to establish a rational foundation for the combination chemotherapy of cancer. The approach is based on the concept of employing combinations of metabolites and antimetabolites to modulate biochemical pathways with the view of achieving maximal cancer cell damage while simultaneously protecting moral host cells from drug toxicity. Much of the basic information upon which a rational for a particular drug combination is based comes from in vitro studies of others. However, since the ultimate utility of a drug combination depends upon the selective achievement of the appropriate modulation(s) of biochemical pathways in vivo, studies in Research Project 2 will be designed to determine the biochemical effect of a given modulating agent on the final activity of the primary effector agent in vivo. Thus, therapeutic results from a particular drug manipulation, obtained as expected on the basis of the biochemical information that prompted that manipulation, will be confirmed on a biochemical level to insure that the biological results are related to the predicted biochemical changes. Unexpected therapeutic results will be explored at the biochemical level to provide new information that will be utilized to alter the drug combination (or schedule) so as to achieve the desired therapeutic advance. (It must be stressed that the NMR and biochemical studies will be performed with tissues obtained from mice undergoing the in vivo therapeutic regimen in question). Of great importance, these in vivo biochemical, pharmacological, and NMR studies will provide guidelines for comparative pharmacological, and biochemical and NMR studies in the clinic (Research Project 3, Clinical Studies) which will be used to adjust promising therapeutic drug regimens for translation from the animal tumor model to cancer patients. The combined in vivo biological and biochemical findings, Project 1 and 2, lead to guidelines for specific clinical trials; feedback from Project 3, Clinical Studies, may suggest new experimental studies and refinements.